Huisgen 1,3-dipolar cycloadditions are exergonic fusion processes that unite two unsaturated reactants (R. Huisgen, in 1,3-Dipolar Cycloaddition Chemistry, (Ed.: A. Padwa), Wiley, New York, 1984, pp. 1-176; and A. Padwa, in Comprehensive Organic Synthesis, (Ed.: B. M. Trost), Pergamon, Oxford, 1991, Vol. 4, pp 1069-1109). For a review of asymmetric 1,3-dipolar cycloaddition reactions, see K. V. Gothelf, et al., Chem. Rev. 1998, 98, 863-909. For a review of synthetic applications of 1,3-dipolar cycloadditions, see J. Mulzer, Org. Synth. Highlights 1991, 77-95. Huisgen 1,3-dipolar cycloadditions provide fast access to an enormous variety of 5-membered heterocycles (a) W.-Q. Fan, et al., in Comprehensive Heterocyclic Chemistry II, (Eds.: A. R. Katritzky, et al.), Pergamon, Oxford, 1996, Vol. 4, pp. 101-126; b) R. N. Butler, in Comprehensive Heterocyclic Chemistry II, (Eds.: A. R. Katritzky, et al.), Pergamon, Oxford, 1996, Vol. 4, pp 621-678; and c) K. Banert, Chem. Ber. 1989, 122, 911-918). The cycloaddition of azides and alkynes to give triazoles is arguably the most useful member of this family (a) R. Huisgen, Pure Appl. Chem. 1989, 61, 613-628; b) R. Huisgen, et al., Chem. Ber. 1967, 100, 2494-2507; c) W. Lwowski, in 1,3-Dipolar Cycloaddition Chemistry, (Ed.: A. Padwa), Wiley, New York, 1984; Vol. 1, Chapter 5; d) J. Bastide, et al., Bull. Soc. Chim. Fr. 1973, 2555-2579; 2871-2887). However, probably because of concerns about the safety of working with organic azides, synthetic chemists, in both pure and applied fields, have not given this transformation the special attention it deserves. Although the actual cycloaddition step may be faster and/or more regioselective for 1,3-dipoles other than azide, the latter is by far the most convenient to introduce and to carry hidden through many synthetic steps. Indeed, it appears to be the only three-atom dipole which is nearly devoid of side reactions.
Azides make only a fleeting appearances in organic synthesis, serving as one of the most reliable means to introduce a nitrogen substituent —R—X→[R—N3]→R—NH2. The azide intermediate is shown in brackets because it is generally reduced straightaway to the amine. Applications which leverage the unique reactivity offered by the azide group itself are disclosed by the following references from the laboratories of Aube, Banert, and Stoddart (a) P. Desai, et al., J. Am. Chem. Soc. 2000, 122, 7226-7232; b) K. Banert, Targets in Heterocyclic Systems 1999, 3, 1-32; K. Banert, Liebigs Ann./Recl. 1997, 2005-18; c) J. Cao, et al., J. Org. Chem. 2000, 65, 1937-46 and references cited therein. Although azide chemistry can be hazardous, the hazard of working with these reagents may be minimized by employing appropriate safety precautions. Azides are chemically important as a crucial functional group for click chemistry (H. C. Kolb, et al., Angew. Chem. Int. Ed. 2001, 40, 2004-2021). The uniqueness of azides for click chemistry purposes arises from the extraordinary stability of these reagents toward H2O, O2, and the majority of organic synthesis conditions. Indeed, organic azides, particularly in the aliphatic series, are exceptionally stable toward the common reactive chemicals, ranging from dioxygen and water to the aqueous solutions of highly-functionalized organic molecules which make up living cells. (E. Saxon, et al., Science 2000, 287, 2007-2010; and K. L. Kiick, et al., Proc. Natl. Acad. Sci. USA 2002, 99, 19-24). The spring-loaded nature of the azide group remains invisible unless a good dipolarophile is favorably presented.
In fact, it was the razor sharp reactivity window for this cycloaddition process which spawned our “in situ click chemistry” ideas—an approach which resulted in discovery of the most potent non-covalent inhibitor of acetylcholinesterase known to date. (W. G. Lewis, et al., Angew. Chem. Int. Ed. 2002, 41, 1053-1057). However, even then the desired triazole-forming cycloaddition may require elevated temperatures and, in any case, usually results in a mixture of the 1,4- and 1,5-regioisomers (FIG. 1A), unless the acetylene component is attached to an electron-withdrawing group such as a carbonyl or perfluoroalkyl (J. Bastide, et al., Bull. Chim. Soc. Fr. 1973, 2294-2296; N. P. Stepanova, et al., Zh. Org. Khim. 1985, 21, 979-983; N. P. Stepanova, et al., Zh. Org. Khim. 1989, 25, 1613-1618; and D. Clarke, et al., J. Chem. Soc. Perkin Trans. I 11997, 1799-1804).
Efforts to control this 1,4-versus 1,5-regioselectivity problem have met with varying success (P. Zanirato, J. Chem. Soc. Perkin Trans. I 11991, 2789-2796; D. J. Hlasta, et al., J. Org. Chem. 1994, 59, 6184-6189; C. A. Booth, et al., Tet. Lett. 1998, 39, 6987-6990; S. J. Howell, et al., Tetrahedron 2001, 57, 4945-4954; W. L. Mock, et al., J. Org. Chem., 1989, 54, 5302-5308; W. L. Mock Top. Curr. Chem. 1995, 175, 1-24; J. Chen, et al., Org. Lett. 2002, 4, 327-329; J. W. Wijnen, et al., Tet. Lett. 1995, 36, 5389-5392; M. P. Repasky, et al., Faraday Discuss. 1998, 110, 379-389).
In one report, copper (I) catalyzed regiospecific synthesis of peptidotriazoles was achieved in organic solvents using free azides and terminal acetylenes attached to a solid support. (C. W. Tornøe, et al., J. Org. Chem. 2002, 67, 3057). Reactants were non-equimolar. An earlier report disclosed the formation, in the presence of copper (I), of a triazole, as a low yield byproduct, from a bifunctional reagent having an acetylene group and an in situ generated azide (G. L'abbe, Bull. Soc. Chim. Belg. 1984, 93, 579-592).